Hepatocarcinogenesis has been often described as a multi-stage process where precursor lesions could progress into early hepatocellular carcinomas (HCC) by accumulating multiple genetic and epigenetic alterations. In order to decipher the molecular events during early liver carcinogenesis we performed microarray profiling on forty-nine nodular liver lesions (24 cirrhotic nodules, 3 low-, 12 high-grade dysplastic nodules and 10 early HCC). In spite of the considerable heterogeneity observed in the regenerative and dysplastic stages, we detected clear expression differences between dysplastic nodules and early HCC including 460 differentially expressed genes. Functional analysis of the significant gene set also implicated that the MYC oncogene might be responsible for many of transcriptomic alterations. Thus, to explore the potential role of MYC activation in the malignant conversion of the pre-neoplastic lesions, we turned to a comparative genomic approach. Expression of MYC and RAS target gene sets derived from transgenic mice as well as from human cell lines was assessed with gene set enrichment analysis (GSEA). Remarkably, the MYC up-regulated gene sets showed enrichment in early HCC versus dysplasia. Presence of the MYC signature significantly correlated with increased expression of CSN5 as well as with the higher overall transcription rate of genes located in the 8q chromosome region. Furthermore, a genomic classifier constructed from MYC target genes could discriminate early HCC from HGDN and LGDN with the accuracy 75-85%. In conclusion, our study successfully identified unique expression patterns associated the progression of early hepatocarcinogenesis and demonstrated that activation of the MYC transcription signature is indispensable for the malignant conversion of pre-neoplastic lesions. Aberrant methylation, consisting of DNA hypomethylation and/or promoter gene CpG hypermethylation, is implicated in the development of a variety of solid tumors, including HCC. We analyzed the global levels of DNA methylation as well as the methylation status of 105 putative tumor suppressor genes and found that the extent of genome-wide hypomethylation and CpG hypermethylation correlates with biological features and clinical outcome of HCC patients.We identified activation of Ras and downstream Ras effectors (ERK, AKT, and RAL) due to epigenetic silencing of inhibitors of the Ras pathway in all HCC. Further,selective inactivation of SPRY1 and -2, DAB2, and SOCS4 and -5 genes and inhibitors of angiogenesis (BNIP3,BNIP3L, IGFBP3, and EGLN2) was associated with poor prognosis. Importantly,several epigenetically silenced putative tumor suppressor genes found in HCC were also inactivated in the nontumorous liver. Our results assign both therapeutic and chemopreventive significance to methylation patterns in human HCC and open the possibility of using molecular targets, including those identified in this study, to effectively inhibit HCC development and progression. Despite rapid growth in gene expression profile data of cancer, identification of few candidate genes for diagnostic markers or therapeutic targets remains a challenge due to the fact that many genes are altered in cancer. Genome-wide screening of genetic alteration has identified many recurrent genomic loci with DNA copy number changes that might harbor potential driver genes for tumorigenesis. However, functional validation of genes reside in these loci is very time-consuming and is impractical when we have hundreds of candidate genomic loci. We have explored genomic correlates of gene expression and copy number and discovered 50 potential driver genes in hepatocellular carcinoma (HCC). Using three independent approaches, we carried out exhaustive search for genes whose expression is best correlated with copy-number alteration and best associated with prognosis of the patients. In addition, unbiased screening of gene expression patterns that are significantly correlated with the 50 driver genes predicted EGFR as one of best therapeutic targets for HCC. Post-translational modification of histones resulting in chromatin remodelling plays a key role in the regulation of gene expression. Also, it is well established that global hypoacetylation of histone H4 is a common hallmark of human tumors and changes in H4 acetylation may occur early in the tumorigenic process. We have recently identified an elevated expression of histone deacetylase 2 (HDAC2) gene in primary human hepatocellular carcinoma (HCC) and HCC derived cell lines. We have now examined the effects of HDAC2 gene knockdown on cell growth and apoptosis in human HCC cell lines. For silencing of HDAC2 gene expression, Huh7 and HepG2 cells were treated with 5 20 nM of three different siRNAs (HDAC2-1, HDAC2-2, and HDAC2-3) directed against HDAC2. Cell growth was then analyzed by MTT and FACS analysis, and apoptosis was estimated by ELISA for detection of ssDNA and caspase activation. The expression of HDAC2 target gene was determined by quantitative real-time RT-PCR. Among the three tested siRNA molecules, the HDAC2-1siRNA was the most effective in inhibiting HCC cell growth when compared to control treatments (untreated and treated with a negative control siRNA). Huh7 and HepG2 cells transfected with 15 nM of HDAC2-1siRNA for 4 days showed about 68% and 71% growth inhibition, respectively, commomly associated accompanying with decreased G2/M cell populations. Inhibition of liver cancer cell growth was due to increased rate of apoptotic cell death which was about 1.9-fold higher than in control cells. The increased level of apoptosis directly correlated with about 65% activation of caspase-3 and about 75% reduction of target mRNA level. Taken together, these results show that HDAC2 is an important regulator of HCC cell growth and survival, and therefore may represent a potential target for human HCC treatment. The variability in the prognosis of individuals with hepatocellular carcinoma (HCC) suggests that HCC may comprise several distinct biological phenotypes. These phenotypes may result from activation of different oncogenic pathways during tumorigenesis and/or from a different cell of origin. We have address whether the transcriptional characteristics of HCC can provide insight into the cellular origin of the tumor. We integrated gene expression data from rat fetal hepatoblasts and adult hepatocytes with HCC from human and mouse models. Individuals with HCC who shared a gene expression pattern with fetal hepatoblasts had a poor prognosis. The gene expression program that distinguished this subtype from other types of HCC included markers of hepatic oval cells, suggesting that HCC of this subtype may arise from hepatic progenitor cells. Analyses of gene networks showed that activation of AP-1 transcription factors in this newly identified HCC subtype might have key roles in tumor development. In this work we have shown that by applying two independent gene expression signatures, we were able to divide individuals with HCC into three subgroups characterized by statistically significant differences in clinical outcome. These findings support the notion that multiple molecular pathways dictate the development and different clinical outcomes of HCC. Our finding also indicates that the molecular features of HCC such as prognostic gene expression signatures are present at the time of diagnosis. Therefore, the use of gene expression profiling promises to improve molecular classification and prediction of outcomes in HCC. Furthermore, molecular stratification of individuals with HCC into homogeneous subgroups may provide opportunities for the development of new treatment modalities